Racemic drugs patenting

It is also noteworthy that some of the chiral drugs introduced as stereochemical mixtures were more complex than the simple racemate. For example, some new agents were marketed as a mixture of two or more racemic mixtures, e. g., labeta-lol 26 (2 racemates, preparation patent 1971) [83], and cyclofhiazide 27 (4 race-... 

Manufacturing of chiral drugs has become increasingly important hrst to improve potency, second to improve yield, and third to extend the patent life for approved drugs based on racemic mixtures. Stereoselective synthetic methods are used to produce chiral drugs. There are three basic methods being applied ... 

All three ADHD-approved chemical entities have at least one chiral center, a feature that has led to a number of interesting syntheses of these compounds over the years. Amphetamine (1) and methylphenidate (2) were discovered before the modern era of asymmetric and enantioselective synthesis, and are sold as racemic, single-enantiomer, and enantio-enriched formulations. Atomoxetine (3), hrst presented in a 1977 Eli Lilly patent, was developed as a single-enantiomer drug (Molloy and Schmiegel, 1977). 

A steady increase in the number of homochiral drugs on world markets has created an increased demand for enantiomerically pure intermediates as well as for enantioselective technologies. Many pharmaceutical companies are pursuing new financial opportunities and gaining improved bargaining positions by producing patent protected and more expensive enantiomeri-cally pure drugs from unprotected racemic pharmaceuticals. 

The bicyclic aminoalcohol, 3-quinuclidinol, is an important synthon for the preparation of cholinergic receptor ligands [23], anesthetics [24], and drugs for the treatment of Alzheimer s disease and asthma [5]. P. Bossard at Lonza AG developed and patented an enantioselective acylation of racemic 3-quinuclidinol using ChiroCLEC -BL, the CLC form of subtilisin (Fig. 5) [25]. The reaction was run in 2-methyl-3-butanol with vinyl butyrate used as the acylating agent. 

Because ibuprofen has been a successful drug on the market for almost 30 years with no patent protection since 1985, there is a widespread competition for commercial production of this product throughout the world. As a result, several practical and economical industrial processes for the manufacture of racemic ibuprofen (14) have been developed and are in operation on commercial scales.38 Most of these processes start with isobutylbenzene (15) and go through an isobutylstyrene3 4 or an acetophenone intermediate.42 The most efficient route is believed to be the Boots-Hoechst-Celanese process, which involves 3 steps from isobutylbenzene, all catalytic, and is 100% atom-efficient (Scheme 6.1).43 44... 

Enzymes often prove to be the catalyst of choice for numerous transformations, and their prowess is particularly noteworthy for the synthesis of chiral molecules. The ability of biocatalysts to impart chirality through conversion of prochiral molecules or by transformation of only one stereoisomer of a racemic mixture stems from the inherent chirality of enzymes. As noted in the introduction to this book (Chapter 1), the chiral drug market is increasing, partly as a result of the need to produce single enantiomers as advocated by the U.S. Food and Drag Administration.1 The ability to extend the patent life of a drug through a racemic switch also plays a role in this increase. An example of a racemic switch is Astra Zeneca s Esomeprazole, a proton pump inhibitor (see Chapter 31).2... 

New commercial opportunities for racemic switching a drug previously marketed as a racemate can be redeveloped and introduced as an enantiomeri-cally pure form, possibly useful for extending patent protection of a key product. 

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